Aging is an important risk factor for most common human diseases, including type 2 diabetes, cardiovascular disease, neurodegeneration and Alzheimer?s Disease (AD). However, centenarians and super centenarians have a lower incidence and severity of age-related diseases including AD and related dementias. As part of the NIA-funded U19 entitled ?Genetic Variant-based Drug Discovery Targeting Conserved Pathways of Aging?, we are exploring this genetic differences between successfully aged, healthy centenarians and control individuals with no family history of extreme longevity. Using the centenarian resource at the Albert Einstein College of Medicine, we identified rare genetic variants associated with conserved mechanisms of healthy longevity that are being evaluated functionally in mouse models of aging, including natural aging, for phenotypes relevant for late-life human health, and subsequently will be used as leads for developing and testing small molecules targeting the pathways affected by these rare variants. As part of this effort, we identified rare, longevity associated two amino acid variants in SIRT6 (N308K and A313S) in centenarians. In addition, three longevity- associated non-coding variants (rs350845, rs350843, rs350846) significantly correlated with increased expression of SIRT6 in different human tissues. SIRT6 is a member of the sirtuin family of stress responsive proteins with deacetylase and mono-ADP ribosyltransferase enzymatic activity. SIRT6 regulates multiple pathways involved with aging including DNA repair, telomere maintenance, inflammation and glycolysis. Mice deficient in SIRT6 show multiple signs of premature aging with a lifespan of only a few months and overexpression of SIRT6 extends lifespan in mouse models of accelerated and natural aging. We demonstrated that the SIRT6 centenarian variant improves several SIRT6 activities including deacetylation of H3K56Ac, but not H3K9Ac, DNA repair, lamin A binding and, in particular, ribosylation activity. Importantly, we demonstrated that the natural sulfated polysaccharide fucoidan from brown algae and seaweed stimulates the ribosylation activity of SIRT6, improves DNA repair and reduces markers of senescence. These results demonstrate that either upregulation or increased activity of SIRT6 promote longevity and healthy aging, possibly due to improved genome maintenance and DNA repair, suggesting that SIRT6 can be a clinically-relevant target in humans. Here we propose to examine the effects of over-expression of human SIRT6 on pathology in natural and accelerated aging murine models of AD as well as test the beneficial effects of the SIRT6 ribosylation activator, fucoidan, on AD disease progression. These genetic and pharmacologic approaches will be accomplished in one year through the use of AAV-mediated gene transfer of A and Tau into SIRT6 over-expressing (Sirt6-OE) mice in both WT and mice with accelerated aging (Ercc1-/?). These proposed experiments will document that increasing SIRT6 expression or ribosylation activity is therapeutic for AD and lead to the development of novel approaches to prevent or treat the disease.